Validations of Top and Novel Susceptibility Variants in All-Age Chinese Patients with Acute Lymphoblastic Leukemia

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ORIGINAL RESEARCH published: 25 August 2020 doi: 10.3389/fgene.2020.01004

Validations of Top and Novel Susceptibility Variants in All-Age Chinese Patients With Acute Lymphoblastic Leukemia

Fei Liao1,2†, Yuanxin Ye2†, Dandan Yin2†, Yun Qin3†, Jiangyan Zhao2, Wanhua Zhang4, Yan Zhang5, Zhujun Deng2, Yuelan Wang2, Binwu Ying2, Lanlan Wang2, Ju Gao1, Edited by: Yang Shu2*, Yiping Zhu1* and Xiaoxi Lu1* Annalisa Lonetti, University of Bologna, Italy 1 Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Pediatric Hematology/Oncology, West China Second Hospital, Sichuan University, Ministry of Education, Chengdu, China, Reviewed by: 2 State Key Laboratory of Biotherapy, Department of Laboratory Medicine, Precision Medicine Center, West China Hospital, Maoxiang Qian, Sichuan University, Chengdu, China, 3 Department of Radiology, West China Hospital, Sichuan University, Chengdu, China, Fudan University, China 4 Department of Hematology and Hematology Research Laboratory, West China Hospital, Sichuan University, Chengdu, Wentao Yang, China, 5 State Key Laboratory of Biotherapy, Department of Thoracic Oncology, Cancer Center, West China Hospital, St. Jude Children’s Research Sichuan University, Chengdu, China Hospital, United States *Correspondence: Yang Shu Through genome-wide association studies (GWAS), multiple inherited predispositions [email protected] to acute lymphoblastic leukemia (ALL) have been identified in children. Most recently, a Yiping Zhu [email protected] novel susceptibility locus at ERG was localized, exhibiting Hispanic-specific manner. Xiaoxi Lu In this study, we conducted a replication study to in all-age Chinese patients (N = [email protected] 451), not only validating the novel ERG locus, but also systematically determining the † These authors have contributed impact of age on association status of the top GWAS signals. We found that single equally to this work nucleotide polymorphisms at ARID5B, IKZF1, CEBPE, PIP4K2A were only significantly Specialty section: associated with ALL susceptibility in childhood patients with no BCR-ABL fusion, while This article was submitted to Human Genomics, GATA3 signal exhibited its significance in adults no matter carrying BCR-ABL fusion a section of the journal or not. Moreover, the novel ERG SNP can be validated in pediatric patients without Frontiers in Genetics both BCR-ABL and ETV6-RUNX1 fusion. Our finding suggests the modifying effects Received: 07 August 2019 of age on genetic predisposition to ALL, and highlights the impact of ERG SNP in Accepted: 06 August 2020 Published: 25 August 2020 Chinese patients.

Citation: Keywords: acute lymphoblastic leukemia, genetic susceptibility, ERG, all-age patients, subtype speciﬁc Liao F, Ye Y, Yin D, Qin Y, Zhao J, Zhang W, Zhang Y, Deng Z, Wang Y, Ying B, Wang L, Gao J, Shu Y, Zhu Y INTRODUCTION and Lu X (2020) Validations of Top and Novel Susceptibility Variants in All-Age Chinese Patients With Acute lymphoblastic leukemia (ALL) is a leading cause of disease-induced death, especially in Acute Lymphoblastic Leukemia. children aged between 2 and 5 years old, and age is negatively related to prognosis and survival Front. Genet. 11:1004. rates of ALL patients according to the clinical statistics. The inferior prognosis of adult ALL patients doi: 10.3389/fgene.2020.01004 is likely to be multifactorial, including the age-related diﬀerences in leukemia blasts and host

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Liao et al. ALL-Related Variants in All-Age Chinese

genomic alterations. Leukemogenesis mechanisms were increase the statistical power (Cai et al., 2017). After filtered considered to be different between children and adults. For out the individuals with missing information of either SNPs example, more frequent somatic BCR-ABL fusion (also known analyzed in this study, genotype information of 10,640 out of as Philadelphia chromosome positive, Ph+) were observed in 11,670 individuals from this public database were used for further adults’ (Inaba et al., 2013). Additionally, racial disparities were association analyses. Comparison were conducted between these also noticed in terms of incidence and treatment outcomes, two control cohorts in terms of risk allele frequencies (RAF). highlighting the importance of age- and ethnicity- related study Because the prevalence of patients with ALL is less than 1 in on leukemogenesis and clinical practice. 10,000 in China, these two control cohorts were combined and By conducting genome-wide association studies (GWASs), considered as non-ALL controls (totally 11,096) for SNPs with we and other independent groups identified multiple top no significant difference. inherited predispositions to acute lymphoblastic leukemia (ALL) This study was approved by Ethnics Committee of West China susceptibility, including single nucleotide polymorphisms (SNPs) Hospital and West China Second Hospital, and informed consent at ARID5B, IKZF1, GATA3 and etc. (Papaemmanuil et al., 2009; was obtained from patients or their guardians, as appropriate. Trevino et al., 2009; Perez-Andreu et al., 2013, 2015; Xu et al., 2013, 2015; Vijayakrishnan and Studd, 2018; Wiemels et al., Statistical Analysis 2018). Association of these SNPs are greatly impacted by clinical All SNPs have passed the quality control based on call rate of the characteristics (e.g., age, ethnicity, and subtypes) (Xu et al., SNPs (at least 95% patients have been successfully genotyped for 2012; Perez-Andreu et al., 2015; Liao et al., 2016). For instance, each SNP), and Hardy-Weinberg equilibrium (P > 0.05 for χ2- we and another independent group noticed that association test). The association of each SNP with ALL susceptibility was of ARID5B and GATA3 SNPs with ALL risk were oppositely estimated by comparing the genotype frequency between ALL influenced by age in Caucasians and Hispanics (Migliorini cases and non-ALL controls by using logistic regression model. et al., 2013; Xu et al., 2013). Also, we recently identified a P-value, odds ratio (OR) and 95% confidence interval (95% CI) novel locus at rs2836365 in ERG gene, which tends to exhibit was estimated by using R (version 3.5), and a two-sided P < 0.05 Hispanic specific manner and varied in different subtypes (Qian was considered as statistically significant. et al., 2018). This novel site has been recently validated in independent studies (de Smith et al., 2019; Vijayakrishnan et al., 2019), but predominately performed in childhood without BCR- RESULTS ABL fusion, with limited systematical investigation in Ph+ adolescents/adults and Chinese patients. Totally 451 B lineage all-age ALL patients were included in In this study, we sought to investigate association of the this study, and were subsequently divided into two age groups, reported top GWAS signals (i.e., ARID5B, IKZF1, GATA3, including 294 childhood (median age = 4.5; ≤ 14 years), and PIP4K2A, CEBPE, and ERG) with ALL susceptibility in all-age 157 adolescents/adults (median age = 37; range 14–68). Baseline Chinese patients, and also estimate the impact of BCR-ABL characteristics of ALL patients are summarized in Table 1. BCR- fusion and age at diagnosis. ABL fusion has been taken it into account in the association test, because it is enriched in adults and barely considered in previous association studies. Totally nine SNPs were directly genotyped in MATERIALS AND METHODS all cases and 456 non-ALL controls, with overall call rate >95%. To increase the statistical power, genotypes of these nine SNPs Subjects and Genotyping were also retrieved from public dataset with 10,640 Han Chinese, Peripheral blood was obtained from 456 non-ALL individuals, and compared with our non-ALL controls in terms of risk allele as well as 451 all-age B-lineage ALL patients, who were treated with standard protocol in Department of Hematology/Oncology, West China Hospital and West China Second Hospital (e.g., TABLE 1 | Characteristics of patients. CCGC-ALL2015, registered in http://www.chictr.org.cn/with ID: Clinical features Children (N = 294) Adults (N = 157) ChiCTR-IPR-14005706) (Zhu et al., 2018; Cao et al., 2020). Clinical information of each patient was obtained from the Age at diagnosis (years); median ± SD 4.5 ± 2.98 37 ± 13.35 electronic records system at our hospitals, including gender, Gender age and white blood cell (WBC) at diagnosis, molecular Male, N (%) 152 (51.7%) 90 (57.3%) subtypes. Fusion-based molecular subtypes were determined Female, N (%) 142 (48.3%) 67 (42.7%) by Fluorescence in situ hybridization, while hyperdiploid was WBC (× 109/L); median ± SD 10.65 ± 67.79 17.03 ± 96.73 determined by flow cytometry-based DNA index. Patients (14 Molecular subtype years is considered as children, while the rest were considered as ETV6-RUNX1 64 1 adolescents/adults (following referred as “Adults”) in this study. TCF3-PBX1 12 2 Nine SNPs at 6 loci (ARID5B, IKZF1, GATA3, PIP4K2A, BCR-ABL (Ph+) 16 91 CEBPE, and ERG) were directly genotyped through Sanger Hyperdiploid* 32 0 sequencing. Additionally, we also retrieved genotype information *Hyperdiploid subtype was not determined in 149 out of 451 patients, because it of a large Chinese Han population from the public dataset to is not routinely tested before 2016, especially in adults.

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TABLE 2 | Comparison of two control cohorts. significance after excluding ETV6-RUNX1 and Ph+ subtypes of patients [P = 0.04, OR = 1.23 (1.01–1.52)], Next, RAF SNP ID Gene RAF of controls P-value of rs2836365 was determined in each ALL subtype and In-House Public control age group. Consistent with observation in Hispanics (Qian (N = 456) (N = 10,640) et al., 2018), enriched risk allele was observed in TCF3-PBX1 subtype at rs2836365 (RAF = 0.36, Figure 1). However, rs10821936 ARID5B 0.366 0.357 0.65 the difference was not significant probably because of the rs7090445 ARID5B 0.364 0.359 0.86 small sample size. rs3824662 GATA3 0.306 0.318 0.56 rs11978267 IKZF1 0.1 0.146 0.23 rs11770117 IKZF1 0.853 0.846 0.73 rs4982731 CEBPE 0.175 0.147 0.13 DISCUSSION rs4748793 PIP4K2A 0.815 0.809 0.6 Racial differences in cancer risk and survivals are well rs7088318 PIP4K2A 0.614 0.589 0.91 documented, but with poor biological basis explored (Schafer rs2836365 ERG 0.262 0.272 0.29 and Hunger, 2011). Although increased genomic screenings were RAF, risk allele frequency. conducted in non-Caucasians, the most comprehensive records and novel findings in cancer genomics are still predominated based on Caucasian but limited in Chinese, including ALL. frequencies (RAF). No significantly difference were observed in In this study, we systematically analyzed the association any of these SNPs, we therefore combined the two control cohorts status of the reported top and novel GWAS signals in all- (N = 11,096) to conduct association analyses (Table 2). age Chinese ALL patients, demonstrating the large effect After comparing the genotype frequency between ALL cases of age on genetic predispositions to ALL susceptibility. and non-ALL controls, six SNPs at 4 loci (i.e., GATA3, ARID5B, The top signal at ARID5B locus exhibited the strongest IKZF1, and CEBPE) were significantly associate with ALL association only in childhood patients, which further susceptibility in all-age patients (Table 3). rs10821936 at ARID5B support its importance in Chinese patients (Wang et al., locus [P = 1.8 × 10−11, OR = 1.59 (1.39–1.81)] was in high lineage 2013). However, no significant association was found in disequilibrium (r2 = 0.98) with rs7090445 [P = 5.3 × 10−10, adolescents/adults, which is consistent with the findings in OR = 1.53 (1.34–1.76)], which was considered to be the potential Caucasians (Peyrouze et al., 2012; Burmeister et al., 2014), as causal variant for ARID5B locus (Studd et al., 2017), whereas well as the fact of negative correlation of ARID5B SNP effect rs11770117 [P = 0.003, OR = 1.41 (1.12–1.76)] at IKZF1 exhibit as with age at diagnosis in pediatric patients (Xu et al., 2013). an independent signal even after adjust for rs11978267 [P = 0.005, In contrast, only GATA3 SNP exhibited its significance in OR = 1.32 (1.09–1.59)] with Padjust = 0.02, which is consistent adolescents/adults, validating previous Caucasian population with our previous observation in Hispanics (Xu et al., 2013). based GWAS performed by us and another independent when BCR-ABL fusion was taken into accounts, SNPs at ARID5B, group. On the other hand, we validated the association of IKZF1 and CEBPE loci lost their significance in Ph+ patients, IKZF1-rs11978267 and CEBPE SNP with ALL risk in childhood while risk allele of rs3824662 at GATA3 locus was overrepresented patients, standing by the side of replication study with positive in both Ph+ patients [P = 0.02, OR = 1.40 (1.07–1.83)] and Ph− validation result (Urayama et al., 2018), rather than the race- patients [P = 0.04, OR = 1.18 (1.01–1.38)] (Table 3). specific assumption (Wang et al., 2013). Moreover, at least We next performed association analyses in two age groups two independent association signals were located at IKZF1 separately. Interestingly, ARID5B and GATA3 SNPs were only locus, and higher impact of rs11770117 than rs11978267 significantly associated with ALL susceptibility in childhood and was noticed in Hispanics but not Caucasians. In this case, adolescent/adult patients, respectively (Table 3). Additionally, IKZF1-rs11770117 was also evaluated in our cohort, and the independent IKZF1 signal exhibit its association in both exhibits not only independent association with childhood ALL age group, with even higher odds ratio in adult than susceptibility after adjusting for rs11978267, but also marginally childhood Ph− patients (1.55 vs. 1.36), while the top IKZF1 significance in adolescents/adults, indicating different regulation SNP (i.e., rs11978267) was only significant in childhood Ph− patterns of IKZF1 may be involved in leukemogenesis between patients (Table 3). SNPs at PIP4K2A locus also tend to children and adults. be associated with ALL susceptibility in childhood patients, Effects of the reported inherited predispositions to ALL varied especially with hyperdiploid subtype [e.g., rs4748793, P = 0.02, among different subtypes. For instance, ARID5B and PIP4K2A OR = 1.93 (1.09–3.40)]. SNPs were more enriched in hyperdiploid subtype, which was Particularly, we focused on the novel Hispanic-specific also validated in our study. However, Ph+ subtype has barely ALL risk signal at ERG locus, observing only marginally mentioned because of its low frequency in childhood ALL. significant association of this SNP with ALL susceptibility In this study, 70 Ph+ patients were enrolled for association in childhood patients [P = 0.09, OR = 1.17 (0.98–1.40)], analyses, and mostly in adolescents/adults. Although no clear but not adults (P = 0.76). Because RAF of rs2836365 was conclusion can be drawn in childhood ALL due to the limited observed to be under-represented in patients with ETV6- statistical power, we observed significant association of GATA3 RUNX1 fusion (Qian et al., 2018), the association reached SNP with ALL risk in adults with Ph+ subtype, indicating its

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Liao et al. ALL-Related Variants in All-Age Chinese 1.44 (1.15–1.80)1.47 (1.04–2.06) 0.32 1.42 (1.06–1.90) 14 years) Control > 0.03 0.02 -value OR (95% CI) RAF 0.001 P ). P-values and odds ratios were estimated by the − , and 66 Ph 1.86 (1.58–2.19) 0.391.91 (1.61–2.26) 0.39 0.17 0.39 1.17 (0.93–1.47) 1.17 (0.82–1.66) 0.36 1.39 (1.12–1.72) 0.151.44 (1.16–1.79) 0.12 0.681.36 0.66 (1.06–1.76) 1.09 (0.73–1.63)1.39 0.9 (1.06–1.81) 1.17 (0.58–2.34) 0.14 0.91 0.061.40 0.17 (1.09–1.79) 1.55 (0.98–2.47) 0.171.41 (1.09–1.82) 1.73 (0.79–3.76) 0.13 0.85 0.52 0.72 1.17 (0.72–1.92) 1.21 (0.43–3.43) 0.15 1.91 (1.60–2.26) 0.371.91 (1.61–2.26) 0.38 0.59 0.68 1.07 (0.85–1.34) 1.08 (0.76–1.54) 0.36 1.23 (1.01–1.52) 0.28 0.91 1.03 (0.62–1.72) + 14 years) Adults ( ≤ 13 13 13 13 − − − − 10 10 10 10 0.02 0.02 0.04 × × × × -value OR (95% CI) RAF 0.002 0.001 0.007 0.009 P 1.8 1.7 2.5 1.7 1.59 (1.39–1.81) 0.51 1.32 (1.09–1.59) 0.18 1.36 (1.10–1.68) 0.18 1.41 (1.12–1.76) 0.88 1.42 (1.11–1.83) 0.88 1.35 (1.08–1.68) 0.2 1.73 (1.49–2.02) 0.51 1.36 (1.06–1.74) 0.2 1.53 (1.34–1.76) 0.51 1.24 (1.09–1.43) 0.351.18 (1.01–1.38) 0.341.40 (1.07–1.83) 0.1 0.38 0.21 1.15 0.5 (0.97–1.36) 1.12 (0.94–1.33) 0.4 0.41 1.28 (0.63–2.58) 0.4 1.71 (1.46–1.99) 0.52 11 12 10 11 − − − − 10 10 10 10 0.02 0.04 0.02 × × × × -value OR (95% CI) RAF 0.005 0.004 0.003 0.006 0.008 0.002 P 1.8 2.7 5.3 1.4 , the rest are not known for Ph status); 157 adults (91 Ph − 0.4 0.3 0.09 1.16 (0.98–1.38) 0.31 0.08 1.18 (0.98–1.41) 0.28 0.82 1.06 (0.64–1.75) 0.49 0.39 0.36 1.14 (0.86–1.50) 0.34 0.870.18 1.06 (0.51–2.20)0.15 0.4 0.29 0.60.89 1.18 (0.87–1.58) 0.88 1.13 (0.72–1.78) 0.29 0.10.19 0.15 1.31 (0.80–2.14) 0.57 0.83 0.870.84 1.41 (0.43–4.64)0.82 0.84 1.05 0.16 (0.62–1.78) 0.12 0.04 0.84 0.380.61 1.10 (0.42–2.87) 1.23 (0.95–1.60) 0.890.62 1.25 (0.76–2.04) 0.18 0.85 1.05 (0.65–1.71) 0.3 0.2 0.75 0.28 3.94 (0.53–28.9) 0.07 1.46 (0.82–2.59) 1.09 0.19 (0.93–1.28) 0.47 1.20 (0.86–1.67) 0.61 1.30 0.32 (0.98–1.72) 0.63 0.76 1.39 (0.57–3.41) 1.32 (0.76–2.31) 0.36 0.84 0.52 0.63 0.53 1.08 1.29 (0.91–1.29) (0.60–2.79) 1.20 (0.57–2.52) 0.62 1.20 (0.67–2.16) 0.62 0.61 0.33 1.13 (0.71–1.79) 1.20 (0.83–1.74) 0.36 0.270.31 0.98 0.08 1.00 (0.70–1.45) 0.23 1.19 (0.98–1.45) 0.32 0.64 1.22 (0.53–2.83) 0.28 0.83 1.04 (0.70–1.57) 0.49 0.37 0.8 1.04 (0.78–1.37) 0.34 0.85 1.07 (0.52–2.22) 0.37 0.72 1.06 (0.78–1.43) RAF − , and 272 Ph + − + − + − + − + − + − + − − + + − + Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph /ETV6-RUNX1 − Ph 0.05 was bold. Chromosomal locations are based on GRCh37/hg19. Chr, chromosome; RAF, risk allele frequency; ference allele (GRCh37/hg19); ALT, alternative allele; OR, odds < 7:50398606 C*/T7:50406065 A*/T all all 0.17 0.89 10:8104208 A*/C all 0.37 10:63723577 C*/T all 0.47 10:22483011 A*/G10:22564019 A/C* all all 0.84 0.13 0.61 1.20 (0.95–1.51) 0.84 0.15 0.1 1.11 (0.96–1.29) 0.61 1.25 (0.96–1.63) 0.82 0.28 0.86 1.10 (0.93–1.30) 1.04 (0.65–1.66) 0.62 0.81 0.28 1.17 (0.88–1.57) 0.59 10:63721176 C*/T all 0.46 14:23585333 C*/T all 0.19 21:39768274 A/G* all 0.3 0.1 1.14 (0.97–1.33) 0.3 0.09 1.17 (0.98–1.40) 0.28 0.76 1.05 (0.77–1.44) 0.27 ERG IKZF1 IKZF1 GATA3 CEBPE ARID5B ARID5B PIP4K2A PIP4K2A Association of the GWAS hits with ALL susceptibility in all-age Chinese patients. ratio; CI, conﬁdence interval. *Asterisk indicates risk allele for ALL susceptibility. additive logistic regression test, P TABLE 3 | SNP ID Genesrs10821936 Location (Chr:Position) Allele Subtype group All age Childhood ( Totally 451 patients can be divided into multiple groups: 294 children (16 Ph rs7090445 rs11978267 rs11770117 rs4982731 rs4748793 rs7088318 rs2836365 rs3824662

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FIGURE 1 | The frequency of ERG SNP in age-aged ALL patients. Risk allele frequencies of rs2836365 were illustrated in all patients/non-ALL controls, and separately in each group divided in terms of age and subtypes. Logistic regression tests were conducted by comparing risk allele frequencies of rs2836365 in each patient group with non-ALL controls. ∗P < 0.05.

broad effect in both Ph+ and Ph-like ALL in elder patients DATA AVAILABILITY STATEMENT (Perez-Andreu et al., 2013). To our knowledge, this is the first report that established the correlation of GATA3 SNP with The raw data supporting the conclusions of this article will be ALL risk in adult Ph+ patients, which therefore requiring more made available by the authors, without undue reservation, to any evidences in independent validation cohorts. qualified researcher. Importantly, we recently identified a novel Hispanic-specific signal at ERG locus, which is highly related to Native Americans ancestry (Qian et al., 2018). Since ancestors of Native Americans ETHICS STATEMENT is considered to descend from a single founding population initially split from East Asians (Moreno-Mayar et al., 2018), The studies involving human participants were reviewed and we sought to evaluate its effect in Chinses ALL patients. approved by the Ethics Committee of West China Hospital Actually, the trend of ERG-rs2836365 RAF distribution in and West China Second Hospital. Written informed consent to each subtype is similar to that in childhood Hispanic patients, participate in this study was provided by the participants’ legal which is high in TCF3-PBX1+ subtype and low in ETV6- guardian/next of kin. RUNX1− subtype, while no difference was observed in adults with any subtypes. Association of ERG-rs2836365 can only reach AUTHOR CONTRIBUTIONS statistically significance in childhood patients with Ph−/ETV6- − RUNX1 , probably because of the small sample size. YS, YiZ, and XL designed and supervised this study. FL, DY, JZ, Collectively, our results not only described association ZD, and YW conducted the experiments and data analyses, and of the top GWAS hits with ALL susceptibility in all-age + interpreted the data. YY, YQ, WZ, YaZ, BY, LW, and JG collected Chinese patient (including Ph patients), but also provided the clinical information. XL contributed to the conception of independent confirmation that the novel signal at ERG locus the study and drafted the manuscript. All authors contributed to conferred risk of childhood ALL in an age and subtype writing of the manuscript and approved the final manuscript. specific manner. Additionally, the fact of consistent significant race-specific association of ERG and IKZF1-rs11770117 with ALL susceptibility, suggests the similarity of East FUNDING Asians and Hispanics for leukemogenesis. However, since the relatively small sample size in our study, additional This work was supported by grants from the National Natural independent cohorts with larger sample size are needed Science Foundation of China (Nos. 81903735, 81902872, and to confirm the effect of ERG SNP, especially in different 81902437), and the National Key Research and Development molecular subtypes. Program of China [No. 2016YFC0905000 (2016YFC0905001)].

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Genetic polymorphisms in ARID5B, CEBPE, IKZF1 and CDKN2A Conflict of Interest: The authors declare that the research was conducted in the in relation with risk of acute lymphoblastic leukaemia in adults: a group for absence of any commercial or financial relationships that could be construed as a research on adult acute Lymphoblastic leukaemia (GRAALL) study. Br. J. potential conflict of interest. Haematol. 159, 599–602. doi: 10.1111/bjh.12063 Qian, M., Xu, H., Perez-Andreu, V., Roberts, K. G., Zhang, H., and Yang, W. Copyright © 2020 Liao, Ye, Yin, Qin, Zhao, Zhang, Zhang, Deng, Wang, Ying, Wang, (2018). Novel susceptibility variants at the ERG locus for childhood acute Gao, Shu, Zhu and Lu. This is an open-access article distributed under the terms lymphoblastic leukemia in hispanics. Blood 133, 724–729. doi: 10.1182/blood- of the Creative Commons Attribution License (CC BY). The use, distribution or 2018-07-862946 reproduction in other forums is permitted, provided the original author(s) and the Schafer, E. S., and Hunger, S. P. (2011). Optimal therapy for acute lymphoblastic copyright owner(s) are credited and that the original publication in this journal leukemia in adolescents and young adults. Nat. Rev. Clin. Oncol. 8:417. doi: is cited, in accordance with accepted academic practice. No use, distribution or 10.1038/nrclinonc.2011.77 reproduction is permitted which does not comply with these terms.

Frontiers in Genetics| www.frontiersin.org 6 August 2020| Volume 11| Article 1004